Medicated stent having multi-layer polymer coating

ABSTRACT

This invention relates to stents having medicated multi-layer hybrid polymer coatings, useful for the treatment of stenosed vasculature or other body passages.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/828,512, filed Jul. 1, 2010, now pending, which is acontinuation-in-part of International Patent Application No.PCT/US02/08039, filed Mar. 18, 2002, which claims priority to U.S.Provisional Patent Application No. 60/276,089, filed Mar. 16, 2001, allof which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to stents having medicated multi-layer hybridpolymer coatings, useful for the treatment of stenosed vasculature orother body passages.

BACKGROUND OF THE INVENTION

Angioplasty procedures have dramatically increased as a treatment foroccluded arteries. However, vessels often experience reclosure followingthe angioplasty procedure. The closure of vessels following angioplastyis known as restenosis. The process of restenosis can occur in over 30%of the cases, depending upon the vessel location, lesion length, as wellas other variables.

Restenosis may be caused in some cases by simple mechanical reflex; e.g.caused by the elastic rebound of the arterial wall and/or by dissectionsin the vessel wall caused by the angioplasty procedure. These mechanicalproblems have been mitigated somewhat by the use of stents to hold openand prevent elastic rebound of the vessel, and reducing the level ofrestenosis for many patients. The stent is typically introduced bycatheter into a vascular lumen and expanded into contact with thestenosed vascular lesion, thereby providing internal support for thevessel wall. Examples of stents, which have been used in the clinicsinclude stents disclosed in U.S. Pat. No. 4,733,665 issued to Palmaz,U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062issued to Wiktor which are incorporated herein by reference in theirentirety.

Another aspect of restenosis is believed to be a natural healingreaction to the injury of the arterial wall that is caused by theangioplasty procedure. The final result of the complex steps of thehealing process is intimal hyperplasia, the migration and proliferationof medial smooth muscle cells, until the vessel is again occluded.

Stents are typically tubular metallic devices, which are thin-metalscreen-like scaffolds, and are inserted in a compressed form and thenexpanded at the target site. The stents are intended to providelong-term support for the expanded vessel, to keep it from restenosingover time. Unfortunately, initial data from the clinic indicates thatthe stent implants are not entirely successful in their mission, and inas many as 30% or more of the cases, the vessel restenoses within oneyear. It would be desirable to have medication(s) available on the stentsurface to cope with problems, which arise on the stent surface or inadjacent patient tissue.

When coronary stents are placed, patients often are subjected toaggressive anti-thrombogenic, anti-platelet regimes in order to preventthrombus formation on the stent surfaces. Thrombus formation on stentsurfaces can be a natural consequence of placement of metal objects inthe vasculature. It is recognized that the thrombi formed on stents maybreak loose from the stent, and produce undesired and dangerousocclusions elsewhere in the vasculature. Unfortunately, an aggressiveanti-thrombogenic regime compromises a patient's ability to healinjuries that accompany the stenting procedure or other collateralprocedures that may have been required. Thus, it is desirable thatmethods be found that reduce the need for the aggressiveanti-thrombogenic therapy associated with coronary stent placement.

To address these problems, various approaches have been proposed. In EP0 706 376 B1, Burt, et al, proposed that paclitaxel could beincorporated in polymeric layers. Examples included polycaprolactam,poly (lactic-co-glycolic acid), and others. However, many of theselayers are biodegradable, and may thus depend upon the enzymaticcomposition of the patient. It is known that the enzymatic compositionsvary considerably from patient to patient. It is thus likely that thebiodegradation process and drug release rate would occur at differentrates from patient to patient. Furthermore, the polymers used in thisdisclosure possess inferior adhesion for this application.

U.S. Pat. No. 5,837,008, Berg, et al., U.S. Pat. No. 5,851,217, Wolff,et al., and U.S. Pat. No. 6,344,035, Chudzik, et al., describeincorporation of drugs in multiple layers of a polymer on stents,wherein the drug-polymer layers are applied in one or more consecutiveapplications. Polymers listed include bioabsorbable and biostableexamples. Bioabsorbable examples listed include poly (L-lactic acid),poly(lactide-co-glycolide), and poly(hydroxybutyrate-co-valerate). Drugslisted include heparin and other anticoagulant agents, glucocorticoid orother anti-inflammatory agents, and various anti-replicate agents.Bioabsorbable polymers may depend on the enzymatic composition of thepatient, and may be subject to patient to patient variation in drugrelease. Also, such polymers possess inferior adhesion for thisapplication. Biostable polymers listed include silicone, polyurethanes,polyesters, vinyl homopolymers and copolymers, acrylate homopolymers andcopolymers, polyethers, and cellulosics. Furthermore, the use of asingle polymer in the drug release layer limits the drug releasedynamics to that enabled by the specific polymer used in the layer, andis thus less able to regulate the drug release dynamics to the sameextent as is possible using hybrid polymer layers. Further, optimizingdrug release dynamics does not provide a coating with the necessaryadhesion and flexibility to be clinically acceptable on a stent.

It has been proposed to provide stents, which are seeded withendothelial cells. In one experiment, sheep endothelial cells that hadundergone retrovirus-mediated gene transfer for either bacterialbeta-galactosidase or human tissue-type plasminogen activator wereseeded onto stainless steel stents and grown until the stents werecovered. The cells could therefore able to be delivered to the vascularwall where they could provide therapeutic proteins. Other methods ofproviding therapeutic substances to the vascular wall include simpleheparin-coated metallic stents, whereby a heparin coating is ionicallyor covalently bonded to the stent.

U.S. Pat. No. 5,843,172 to Yan, describes a porous metallic stent inwhich medication is loaded into the pores of the metal. The stent mayalso have a polymeric cover, which would contain a different drug thanthe drug that was loaded into the metal pores. This has the ability todeliver more than one drug, but the ability to mediate the drug releasedynamics is limited by the fact that only one type of polymer is used,and the drug in the metallic pores is not bound in a polymeric medium.It has been found that the use of pores without polymer entrapment ofthe drug results in the drug release rate/profile being entirelydependent on the drug solubility.

Finally, Von Bergelen et al. “The JOSTENT™ Coronary Stent Graft-JustAnother Stent? . . . or How Should it be Implanted?”, Abstract: 825-4,ACC 2000/49^(th) Annual Scientific Session, Mar. 12-15, 2000, Anaheim,Calif., USA, describes a sleeve of two stents with an ultra thin PTFEtube there between, which was implanted in 24 patients who had sufferedacute coronary ruptures. This method mandates the use of oversizedhigh-pressure balloon catheters to achieve adequate expansion of thisnew coronary stent graft (CSG). In addition, the endoprosthsesis must beaccurately sized and placed to avoid occlusion of side branchesoriginating from the target lesion segment, and thrombus formation is aconcern.

Thus, there is a need for technology that can consistently providetherapeutic activity from the surfaces of stents in order to reduce theincidence of restenosis and thrombus formation after coronary stentingprocedures in the clinic.

SUMMARY OF THE INVENTION

In one embodiment, the present invention comprises a stent on whichmultiple polymer layers are applied to the stent surfaces, at least one(but not all) of which polymer layers provide reservoirs for a varietyof individual drugs or drug cocktails. The polymer layers may be hybridpolymer layers, and may serve different purposes in the multi-layerstent coating.

The polymer layers of the invention typically comprise a bonding orprimer layer, which can be applied directly onto the metallic stentsurface. An intermediate polymer layer optionally can be applied overthe primer layer. The intermediate polymer layer is used to enhance theflexibility, elasticity, and expandability of the composite hybridpolymer layers. Next, one or more drug carrier polymer layers can beapplied over the intermediate layer, or if an intermediate layer is notused, directly onto the primer layer. One or more of the polymer layersmay be a hybrid polymer layer. As used herein, a hybrid polymer layer isone in which two or more different polymers are combined forming alayer, which is a homogeneous polymeric alloy. In the instant invention,a primer hybrid polymer contains polymers designed to provide anchorageto the stent surface. An intermediate hybrid polymer layer containspolymers capable of imparting enhanced flexibility and elasticity to thecoating composite and adhesion to the primer and to the drug releaselayers. The drug release layer preferably is also a hybrid polymerlayer, but contains different polymers from those used in the other twolayers.

The polymer layers of the invention possess excellent flexibility andelasticity, and they are expandable, so as to remain intact followingsterilization, implantation in the patient, and stent expansion. Thepolymer layers are not significantly bioerodable, so that differences inhormonal activity from patient to patient are minimized. The polymerlayers can regulate drug release dynamics because hydrophilic andhydrophobic polymers are employed.

The drug-loaded layers of the invention provide technology forentrapping therapeutic drug mixtures in designed, biocompatible, hybridpolymer layers. In one embodiment of the invention, the polymer layersserve as reservoirs for the drugs, and protect and stabilize the drugsduring sterilization and storage. The polymer layers can be porous tobody fluids, such that the drugs can become solubilized via diffusion ofbody fluids into the polymer layers, with subsequent diffusion of thesolubilized drugs out of the layers at controlled rates. Thepolymer-drug layers can be deposited over the polymeric coated stentscaffolds, which can be deliverable to stenosed lesions via catheters,such as in the manner currently practiced in the clinic. The polymerlayers are designed to provide efficacious drug concentrations forappropriate time periods at the stenosed site. For example, drug-polymerlayers may provide fast drug release for about one to three days,followed by a slower sustained drug release rate for one week, twoweeks, 30 days or longer, as needed. The sum of the periods of fast andslow release may be referred to as a sustained period. The drug releaselayers can also be designed to provide different drug release rateprofiles, if desired, by for instance adjusting the ratio of hydrophilicto hydrophobic polymers in the polymer drug release layer.

In one embodiment of the invention, the polymer layers comprisepolymeric alloys of polyvinylpyrrolidone, cellulose esters, andpolyurethanes, acrylate polymers and copolymers, polyethylene glycols,polyethylene oxides, hydrophilic acrylate polymers and copolymers,melamines or epoxides in order to alter diffusion dynamics, or toenhance physical properties such as adhesion, flexibility, and abrasionresistance by varying the components in the casting solution (especiallythe ratio of hydrophilic to hydrophobic polymers). It is contemplatedthat for a faster drug release, a higher ratio of hydrophilic polymer tohydrophobic polymer would be used and visa versa to slow the drugrelease.

In another embodiment of the invention, the surface properties of thecoating can be further influenced by its relative composition, havingvarying degrees for example, from highly lubricious to essentiallynon-lubricious. By including pharmacological agents in the surfacelayer, the surface can become a drug reservoir and provide high regionaldrug concentrations, while systemic concentrations remain low. Suchpolymeric alloys are described herein, and also in U.S. Pat. No.5,069,899, Whitbourne, et al., titled “Anti-thrombogenic, anti-microbialcompositions containing heparin;” U.S. Pat. No. 5,525,348, Whitbourne,et al., titled “Coating compositions comprising pharmaceutical agents;”U.S. Pat. No. 6,086,547, Hanssen, et al., titled “Wire for medical usecoated with polyether sulphone and a copolymer;” and U.S. Pat. No.6,110,483, Whitbourne, et al., titled “Adherent, flexible hydrogel andmedicated coatings;” published PCT international application WO 01/15526titled “Anti-infective covering for percutaneous and vascular accessdevices and coating method;” U.S. Ser. No. 09/442,891, filed Nov. 18,1999, titled “Flexible sealed coil-like devices;” and U.S. Ser. No.60/196,781, provisional application filed Apr. 13, 2001, titled“Targeted therapeutic agent release devices and methods of making andusing the same,” which are incorporated herein by reference.

The coating composition can be used to coat a variety of stents.Non-limiting examples include: either self-expanding stents (such as theWallstent variety), or balloon-expandable stents (as are available in avariety of styles, for instance, Gianturco-Roubin, Palmaz-Shatz, Wiktor,Strecker, Cordis, AVE Micro Stent, Boston Scientific Nir stent, andGuidant MULTI-LINK® coronary stent). The stents are typically preparedfrom materials such as stainless steel or tantalum, or nitinol. Theyhave various mesh patterns having sharp edges, and are shorter or longerand have lower or higher diameters. The coatings of the invention aresuitable for all such stents and others known to those of skill in theart or to be subsequently developed.

One embodiment of the invention relates to a medicated stent having acoating comprising: (a) a primer layer comprising a first composition ofone or more polymers, and (b) a drug reservoir layer comprising a secondcomposition of one or more polymers, the polymer composition of the drugreservoir layer being distinct from the polymer composition of theprimer layer, and the drug reservoir layer further comprising one ormore active agents, the coating remaining intact upon stent expansionand during a sustained period thereafter, and releasing efficaciousamounts of the active agent at the site of stent expansion.

In another embodiment, the medicated stent can further comprise anintermediate layer between the primer layer and the drug release layer,comprising a polymer composition distinct from the polymer compositionof the primer and drug reservoir layers. This medicated stent mayfurther comprise one or more image enhancing material(s) in one of thelayers, or in a separate layer(s), that is capable of enhancingvisibility if the device under ultra sound, magnetic resonance imaging,X ray imaging, and/or other imaging modality.

The medicated stent may comprise different agents that are containedwithin the same and/or different layers. The primer layer and/or thedrug reservoir layer may be a single layer or may comprise two or morelayers. Moreover, the intermediate layer may comprise multiple layers.The medicated stent may comprise more than one active agent.

In yet another embodiment, the primer layer comprises one or morepolymers selected from the group consisting of acrylatepolymer/copolymer, acrylate carboxyl and/or hydroxyl copolymer,polyvinylpyrrolidone/vinylacetate copolymer (PVP/VA), olefin acrylicacid copolymer, ethylene acrylic acid copolymer, epoxy polymer,polyethylene glycol, polyethylene oxide, polyvinylpyridine copolymers,polyamide polymers/copolymers polyimide polymers/copolymers, and/orpolyether sulfones. The intermediate layer may comprise one or morepolymers selected from the group consisting of acrylatepolymer/copolymer, acrylate carboxyl and/or hydroxyl, PVP/VA,polyurethane, silicone urethane polymer, polycarbonate urethane polymer,polyvinylbutyral, and/or epoxy polymers.

The primer and/or intermediate and/or drug reservoir layer may compriseone or more polymer selected from the group consisting of polyurethane,polycarbonate urethane polymer, and silicone urethane polymer.

In a further embodiment, the medicated stent may comprise one or morepolymers having a flexural modulus greater that 1000 psi and elongationat break greater than 200%. The medicated stent may have a drugreservoir layer comprising a polymer selected from acrylatepolymer/copolymer, acrylate hydroxyl and/or carboxyl copolymer,polyvinyl pyrrolidone (PVP), PVP/VA, cellulose ester, polyurethane,polycarbonate-urethane polymer, silicone-urethane polymer, epoxypolymer, polyethylene glycol and/or polyethylene oxide. The medicatedstent may have a drug reservoir comprising one or more polyurethanes,cellulose nitrate, and/or one or more other cellulose ester polymer(s).

In a further embodiment, the medicated stent may have a drug reservoirlayer comprising one or more polymers selected from acrylatepolymer/copolymer, acrylate polymer/copolymer containing carboxyl and/orhydroxyl groups, cellulose nitrate and/or other cellulose ester. Themedicated stent may have an active agent comprising an anti-restenoticagent effective at a stented site. The total coating thickness may bebetween about 0.3 and about 30 microns. The medicated stent may alsohave a primer layer having a thickness between about 0.1 and about 5microns, and the drug reservoir layer having a thickness of betweenabout 0.1 and about 10 microns. Moreover, the medicated stent maycomprise an intermediate layer having a thickness between about 0.1 andabout 15 microns.

In other embodiments of the invention, the active agent is selected fromone or more of anti-thrombogenic agents, anti-inflammatory agents,antineoplastic agents, anti-proliferative agents, cytostatic agents,cytotoxic agents, antimicrobial agents, anti-restenotic agents,anti-platelet agents, and anti-coagulant agents. The active agent mayalso be selected from one or more of anti-fibrin and fibrinolyticagents, anti-platelet agents, prostacyclins (and analogues),glycoprotein IIb/IIIa agents, thromboxane inhibitors, anti-thrombin andanti-coagulant agents, anti-mitotic, antiproliferative and cytostaticagents, antiangiogenic and angiostatic agents, ACE inhibitors, growthfactor antagonists, antioxidants, vitamins, calcium channel blockers,fish oil (omega 3-fatty acid), phosphodiesterase inhibitors, nitric aciddonor, Somatostatin analogues, immunosuppresives and antiinflamatoryagents, antimicrobials, radionuclides including alpha, beta and gammaemitting isotopes, COX-2 inhibitors, endothelial promoters, kinaseinhibitors, epidermal growth factor kinase inhibitors, tyrosine kinaseinhibitors, MAP kinase inhibitors, protein transferase inhibitors, aloneor in combinations.

In a further embodiment, the active agent may be selected from one ormore of plasmin, streptokinase, single chain urokinase, urokinase, t-PA(tissue type plasminogen activator), aminocaproic acid, aspirin,monoclonal antibodies, peptides, drugs (e.g. ReoPro, Cilastagel,eptifibatide, tirofiban, ticlopidine, Vapiprost, dipyridamole,forskolin, angiopeptin, argatroban, dextan, heparin, LMW heparin,Enoxaparin, Dalteparin, hirudin, recombinant hirudin, anti-thrombin,synthetic antithrombins, thrombin inhibitors, Warfarin, other coumarins,vincristine, vinblastine, paclitaxel and its analogues, methotrexate,cisplatin, fluorouracil, rapamycin, azathioprine, cyclophosphamide,mycophenolic acid, corticosteroids, colchicine, nitroprusside,paclitaxel, angiostatin and endostatin; genetic materials,oligonucleotides, Cilazapril, Lisinopril, Captopril, VEGF, FGF,Probucol, Tocopherol, nifedipine, dipyridamole, Molsidomine,angiopeptin, prednisolone, glucocorticoid, dexamethasone, rifamycin,Re-188, Re-186, 1-125, Y-90 celecoxib, Vioxx, dipyridamole,theophylline, alone or in combinations.

In another embodiment, the medicated stent may have a primer layercomprising one or more of acrylate/carboxyl polymer, epoxy polymer,polyvinylpyrrolidone vinylacetate copolymer (PVP/VA). The primer layermay also comprise one or more of ethylene acrylic acid copolymer (EAA),epoxy polymer, and polycarbonate urethane.

In yet a different embodiment of the invention, the intermediate layermay comprise polycarbonate polyurethane. The medicated stent may have adrug release layer comprising one or more of acrylate/carboxyl polymer,epoxy polymer, and polyvinylpyrrolidone vinylacetate copolymer (PVP/VA).The drug release layer may comprise nitrocellulose. The drug releaselayer may also comprise nitrocellulose and one or more ofpolytetramethylene ether glycol urethane, polycarbonate-urethane,silicone-urethane polymer, polyethylene glycol,polymethylmethacrylate-2-hydroxyethylmethacrylate copolymer,polyethylmethacrylate-2-hydroxyethylmethacrylate copolymer,polypropylmethacrylate-2-hydroxyethylmethacrylate copolymer,polybutylmethacrylate-2-hydroxyethylmethacrylate copolymer,polymethylacrylate-2-hydroxyethylmethacrylate copolymer,polyethylacrylate-2-hydroxyethylmethacrylate copolymer,polypropylacrylate-2-hydroxymethacrylate copolymer,polybutylacrylate-2-hydroxyethylmethacrylate copolymer, methylvinylethermaleicanhydride copolymer, and poly (2-hydroxyethyl methacrylate). Theactive agent may be selected from the group consisting of paclitaxel,heparin complexes, rifamycin, and methotrexate.

Another aspect of the invention relates to a method for making amedicated stent having struts becoming separated upon stent expansion,comprising: applying a primer polymer liquid comprising one or morepolymers in a volatile medium, applying a drug reservoir polymer liquidcomprising one or more polymers in a volatile medium, the one or moredrug reservoir polymers being different from the one or more primerlayer polymers, and applying an active agent either together with orafter applying the drug reservoir polymer liquid, and removing thevolatile media, the layers being applied without forming coating bridgesbetween struts of the stent, the layers remaining intact upon stentexpansion, and releasing efficacious amounts of the active agent at thesite of stent expansion. Other embodiments may require more than oneactive agent to be applied or repeating one or more of the applyingsteps. The invention may involve application of an intermediateflexibilizing polymer liquid comprising one or more polymers that differfrom the one ore more polymers of the primer layer and the drugreservoir layer. The volatile media may have a boiling point greaterthan about 110 degrees C. The liquids may have a viscosity between about20 and about 70 cps.

In yet another aspect, the invention relates to a method for making amedicated stent comprising applying a primer polymer layer and a drugreservoir layer comprising at least two polymers and one or more activeagent(s), wherein the polymer compositions of the primer and drugreservoir are different, without forming coating bridges between strutsof the stent, the coating remaining intact upon stent expansion, andreleasing efficacious amounts of the active agent(s) at the site ofstent expansion.

In a further aspect, the invention relates to a method for administeringa bioactive agent to a target site in a subject, comprising: implantinga stent at the target site of the subject, the stent comprising acoating having a primer layer and a drug release layer, the drug releaselayer comprising the bioactive agent, and the primer and drug releaselayers comprising different polymers, expanding the stent, and allowingthe bioactive agent to elute from the coating during an extended period,the coating remaining intact during implanting, during stent expansion,and during the extended period.

The invention also relates to a medicated stent comprising: a stentbody, a biologically active agent, means for containing and controllablyreleasing the agent from the stent over an extended period, comprising afirst polymer, and means for bonding the containing means to the stentbody, comprising a second polymer, the containing and bonding meansremaining intact upon stent expansion and during the extended period.

The elements of the invention recited herein may be combined oreliminated among the particular embodiments described, as would beapparent to a person of ordinary skill.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1, which contains data from Table 1, Example 1 shows the cumulativequantity of paclitaxel eluted, in micrograms, over a period of 336 hours(14 days). Approximately 10% of the paclitaxel eluted out over a periodof 14 days. The total amount of eluted drug and length of elution timeare influenced by the amount of or the number of coatings of the drugreleasing layer, the hydrophilicity of the layer(s), and the solubilityof the drug(s) in the medium into which it/they are being released.

DETAILED DESCRIPTION OF THE INVENTION

In describing preferred embodiments of the present invention, specificterminology is employed for the sake of clarity. However, the inventionis not intended to be limited to the specific terminology so selected.It is to be understood that each specific element includes all technicalequivalents, which operate in a similar manner to accomplish a similarpurpose. The embodiments of the invention may be modified or varied, andelements added or omitted, without departing from the invention, asappreciated by those skilled in the art in light of the above teachings.Each reference cited here is incorporated by reference as if each wereindividually incorporated by reference.

In order to develop a hybrid polymer delivery system for targetedtherapy, it is important to be able to control and manipulate theproperties of the system both in terms of its physical and drug releasecharacteristics. The active agents can be imbibed into a surface hybridpolymer layer, or incorporated directly into the hybrid polymer coatingsolutions. Imbibing drugs into surface polymer layers is an efficientmethod for evaluating polymer-drug performance in the laboratory, butfor commercial production it may be preferred for the polymer and drugto be premixed in the casting mixture. Greater efficacy can be achievedby combining the two elements in the coating mixtures in order tocontrol the ratio of active agent to polymer in the coatings. Suchratios are important parameters to the final properties of the medicatedlayers, i.e., they allow for better control of active agentconcentration and duration of pharmacological activity.

Typical polymers used in the drug-release system can includewater-insoluble cellulose esters, various polyurethane polymersincluding hydrophilic and hydrophobic versions, hydrophilic polymerssuch as polyethylene glycol (PEG), polyethylene oxide (PEO),polyvinylpyrrolidone (PVP), PVP copolymers such as vinyl acetate,hydroxyethyl methacrylate (HEMA) and copolymers such asmethylmethacrylate (PMMA-HEMA), and other hydrophilic and hydrophobicacrylate polymers and copolymers containing functional groups such ascarboxyl and/or hydroxyl.

Cellulose esters such as cellulose acetate, cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate, andcellulose nitrate may be used. The cellulose ester preferably serves asa polymer component in the hybrid polymer compositions. Cellulosenitrate is preferred because of its compatibility with the active agentsand its ability to impart non-tackiness and cohesiveness to thecoatings. Cellulose nitrate has been shown to stabilize entrapped drugsin ambient and processing conditions. Cellulose nitrate (nitrogencontent=11.8-12.2%) preferably is used in this invention, althoughgrades of the polymer having lower nitrate concentrations could be used.Viscosity grades, such as 3.5, 0.5 or 0.25 seconds, are used in order toprovide proper rheological properties when combined with the coatingsolids used in these formulations. Higher or lower viscosity gradescould be used. However, the higher viscosity grades can be moredifficult to use because of the high viscosities that obtain at thesolids concentrations preferred in this invention. Lower viscositygrades, such as 3.5, 0.5 or 0.25 seconds, preferably are used in orderto provide proper rheological properties when combined with the coatingsolids used in these formulations. Physical properties such as tensilestrength, elongation, flexibility, and softening point are related toviscosity (molecular weight) and can decrease with the lower molecularweight species, especially below the 0.25 second grades.

The cellulose derivatives comprise anhydroglucose structures. Cellulosenitrate is a hydrophobic, water-insoluble polymer, and has high waterresistance properties. This structure leads to high compatibility withmany active agents, accounting for the high degree of stabilizationprovided to drugs entrapped in cellulose nitrate. The structure ofnitrocellulose is given below:

Cellulose nitrate is a hard, relatively inflexible polymer, and haslimited adhesion to many polymers that are typically used to makemedical devices. Also, control of drug elution dynamics is limited ifonly one polymer is used in the binding matrix, since the stent hassignificant variables such as coating thickness and the ratio of polymerto entrapped drug. In one embodiment, this invention uses polyurethanepolymers with cellulose nitrate in the hybrid polymer drug loadedmatrix. Polyurethanes provide the hybrid polymer matrix with greaterflexibility and adhesion to the polymer coated stent surfaces of theinvention. Polyurethanes can also be used to slow the drug elution fromcoatings. Aliphatic, aromatic, polytetramethylene ether glycol, andpolycarbonate are among the polyurethanes, which can be used in thecoatings.

From the structure below, it is possible to see how more or lesshydrophilic polyurethane polymers may be created based on the number ofhydrophilic groups contained in the polymer structures. Thepolyurethanes used in the invention are water-insoluble, flexible, andcompatible with the cellulose esters.

Polyvinylpyrrolidone (PVP) is a polyamide that possesses unusualcomplexing and colloidal properties and is essentially physiologicallyinert. PVP and other hydrophilic polymers are typically biocompatible.PVP is incorporated in drug loaded hybrid polymer compositions in orderto increase drug release rates. In one embodiment, the concentration ofPVP that is used in drug loaded hybrid polymer compositions can be lessthan 20%. This concentration would not make the layers bioerodable orlubricious. In addition, PVP concentrations from <1% to greater than 80%are deemed workable.

Acrylate polymers and copolymers including polymethylmethacrylate (PMMA)and polymethylmethacrylate hydroxyethyl methacrylate (PMMA/HEMA) areknown for their biocompatibility as a result of their widespread use incontact and intraocular lens applications. Some work describing the useof such copolymers in drug release coatings for stents has been reportedin the literature. The coating was found to provoke very little smoothmuscle and endothelial cell growth, and very low inflammatory response(Bar). These polymers/copolymers are compatible with drugs and the otherpolymers and layers of the instant invention.

The drug-loaded coatings can be prepared as coating solutions in organicsolvents. The solutions are non-reactive and can have a shelf life of upto 18 months when stored at room temperature. Among others, simpleprocedures (such as dipping or spraying, followed by air-drying) can beused to apply the hybrid polymer surfaces to stents. Drying the devicesat elevated temperatures (40 to 120° C.) can remove the residualsolvents to produce biocompatible surface layers of approximately 0.3 to30 microns thick. Once dried, the surface layers are stable forsubstantially the life of the sterile packaging, generally three to fiveyears, depending on the drug(s) entrapped in the hybrid polymer layer,and on the storage conditions.

The polymers used in the primer layer may be cross-linkable and thecoating may comprise a cross-linker for the polymers, such as epoxyresin, melamine resin, other amino resin, and phenolic resins. Thepolymers may be selected from a carboxyl function acrylic polymer,hydroxyl function acrylic polymer, amine function acrylic polymer,methylol function, and amide function acrylic polymer. They may be across-linkable acrylic selected from methylmethacrylate,butylmethacrylate, isobutylmethacrylate, ethylmethacrylate,methylacrylate, ethylacrylate, butyl acrylate acrylic acid, methacrylicacid, styrene methacrylate, and styrene acrylate, and copolymersthereof, and other non-acrylic polymers such as polyurethanes,polycarbonate-urethanes, silicone-urethanes, aliphatic polyurethanes,polyvinyl pyridine copolymers, polyethylene glycol, polyethylene oxide,polyamide copolymer, polyimide copolymer, other polymers known to thoseof skill in the art may be used in the primer layer.

The primer layer comprises hydrophobic polymers that are preferablywater-insoluble polymers that do not significantly react with thehydrophilic polymers in solution, have low water absorption, provide ahigh degree of flexibility, and have improved bonding to stentsubstrates. Suitable commercial products that may be used in theinvention include acrylics such as ACRYLOID® (Rohm & Haas) AT-63, AT-51,AT-81, WR-97; ethylene acrylic acid copolymers such as PRIMACOR™ (DOW)5989, 5990; melamine resins such as CYMEL®® hexamethoxymethylmelamine(CYTEC Industries) 303, 370, 380; epoxies such as EPON (Shell) 1001; andpolyvinylbutyral such as BUTVAR B-79 (Monsanto), polyurethanes suchTecoflex 93A, Chronoflex AR. The preferred acrylic stabilizing polymersinclude reactive groups such as hydroxyl or carboxyl that can react withepoxies but do not render the polymer hydrophilic.

In one embodiment, the inventive coating includes a hydrophilic polymerused in the primer and/or the drug reservoir layer(s), such as a watersoluble polyolefin such as a hydrophilic vinyl polymer having polarpendant groups, a polyacrylate or methacrylate having hydrophilicesterifying groups, a polyether, a polyethylene glycol, or other polymerwith hydrophilic characteristics as known in the art. The hydrophilicpolymer is preferably PVP or PVP/vinyl acetate such as PVP/VA (GAF)E-335 and E-635.

The hydrophilic component may be of any of the classes discussed inConcise Encyclopedia of Polymer Science and Engineering, Kroschwitz, ed.(Wiley 1990), pp. 458-59, which is incorporated herein by reference.Polymers such as polyvinylpyrrolidone, polyethylene glycol, polyethyleneoxide, or polyvinyl alcohol are acceptable, alone or in combination.Examples of suitable hydrophilic polymers include homopolymers orcopolymers of the following compounds: polyolefins such as vinylpolymers having polar pendant groups, N-vinylpyrrolidone, N-vinyllactam,N-vinyl butyrolactam, N-vinyl caprolactam, sodium styrene sulfonatemonomer, 2-acrylamido-2-methylpropane sulfonic acid, sodium vinylsulfonate, vinyl pyridine, acrylates or methacrylates having hydrophilicesterifying groups. Other hydrophilic polymers include polyethers,polyethylene glycol, polysaccharides, hydrophilic polyurethanes,polyhydroxyacrylates, polymethacrylates, and copolymers of vinylcompounds and hydroxyacrylates or acrylic acid, so long as theappropriate hydrophilicity is present. Other examples include dextran,xanthan, hydroxypropyl cellulose, methyl cellulose, polyacrylamide, andpolypeptides. Other hydrophilic components are known to persons of skillin the art.

The invention may require acrylics, e.g. polymers and copolymers ofacrylic acid and methacrylic acid and esters thereof, as defined forexample in ACRYLOID Thermoplastic Acrylic Ester Resins for IndustrialFinishing, Rohm & Haas, Bulletin 82A37 (1987), including cross-linkableacrylics with at least one component containing carboxyl, hydroxyl,amide, or methylol groups. The following ACRYLOID polymers withfunctional groups given are preferred: AT-51 (hydroxyl), AT-63(hydroxyl), AT-81 (carboxyl), and WR-97 (hydroxyl). Cross-linkableacrylic emulsions such as RHOPLEX B-15J (Rohm & Haas), and styreneacrylic emulsions such as AROLON® 820-W-49 (Reichhold) may also be used.

A variety of polymers may be used, e.g., epoxy resins, particularlycured epoxy polymers such as EPOTUF® 38-505 (Reichhold), and preferablythose cured with polyamide, such as EPOTUF® 37-618 (Reichhold), vinylpolymers, particularly vinyl acetate, vinyl acetals such as polyvinylbutyral, and ethylene vinyl acetate copolymers. Other appropriatepolymers having the requisite characteristics will be apparent topersons of ordinary skill. The polymers preferably, but not necessarily,contain reactive groups or points of reactivity such as hydroxyls,mono-, di- and tertiary amines, acids such as carboxyl, amides, or othergroups which represent points of chemical reactivity. In the case of theacrylics, this is referred to as having a “functionality” that iscross-linkable. The polymers and points of chemical reactivity are ableto form attractive forces such as hydrogen bonding toward the medicaldevice surface, and also toward the hydrophilic polymer and/or bioactiveagent. Such bonds are very strong, and provide desirable adhesion andflexibility to the coating presumably without requiring covalent, ionic,or other links.

Polymers with reactive groups are preferred in the primer layer withstents, which present a metal substrate. However, polymers lacking suchgroups such as acrylic or styrene copolymers may also be usedeffectively. The reactive groups can also react to form a cross-linkedmatrix or help to form a cross-linked matrix. If desired, cross-linkerssuch as urea resins, melamines, isocyanates, phenolics, and others maybe incorporated to interact with the points of chemical reactivity onthe polymer chains to cross-link the polymers of the invention withthemselves. Alternatively, cross-linkers may react with themselves asstabilizing polymers to form a cross-linked matrix in which thehydrophilic polymer is enmeshed, resulting in an adherent, flexiblecoating. Cross-linking is useful in promoting effective adhesion byensuring that the solvents do not attack and degrade the polymer layerexcessively when subsequent layers are applied.

The drug reservoir layer comprises mixtures of more and less hydrophilicpolymers. Hydrophobic polymers comprise cellulose esters such ascellulose nitrate, polycarbonate-urethanes, acrylate polymers andcopolymers with or without functional groups such as those previouslycited in this disclosure. Hydrophilic polymers comprise vinyl polymerswith hydrophilic pendant groups such PVP and its copolymers,polyethylene glycol, polyethylene oxide, HEMA, HEMA-acrylate andmethacrylate copolymers, and other hydrophilic polymers/copolymerspreviously cited in this disclosure.

The coatings of the present invention are extremely durable, even whensubjected to adhesion and flexing tests, as shown in the examples. Suchenhanced adhesion and flexibility is a surprising result. The coatingsaccording to the invention may be applied to the surface of a biomedicaldevice or other device with sufficient thickness and permanence toretain the coating's desirable qualities throughout the useful life ofthe coated device. The coatings of the invention are nonreactive withliving tissue and are non-thrombogenic in blood. They are notsubstantially biodegradable.

The coatings of the invention may be thin, on the order of 0.9 to 100microns, preferably less than about 50 or 30 microns, and coherent inthat they form a continuous surface layer on the stent as manufactured,and retain the coherence on the stent after expansion. They areresistant to removal on prolonged soaking in aqueous fluids, and areadherent to a wide variety of substrates.

The coatings may be applied by various techniques such as dip, pour,pump, spray, brush, wipe, or other methods known to those skilled in theart. The coating solutions have low viscosities, typically less than 100CPS, and have good spreading properties. The coatings are preferablybaked at elevated temperatures, typically 50 degrees C. to 140 degreesC., to drive off the organic solvents. It may be necessary to treat somesurfaces like polyethylene with gas plasma or other ionizing treatmentto promote interaction with the coating and adhesion to the substrates.

The coating may contain polymers in addition to the stabilizing polymersuch as polyurethane, polyester, styrene polybutadiene, polyvinylidenechloride, polycarbonate, and polyvinyl chloride, preferably in the innerlayer to promote adhesion to the surface of the device.

Anti-Restenosis and Other Active Agents

Examples of active agents that be combined with the hybrid polymercarrier layers of the invention include anti-fibrin and fibrinolyticagents, including plasmin, streptokinase, single chain urokinase,urokinase, t-PA (tissue type plasminogen activator), aminocaproic acid;anti-platelet agents including, aspirin, prostacyclins (and analogues);glycoprotein IIb/IIIa agents including monoclonal antibodies, peptides(e.g. ReoPro, Cilastagel, eptifibatide, tirofiban, ticlopidine,Vapiprost, dipyridamole, forskolin, angiopeptin, argatroban),thromboxane inhibitors; anti-thrombin and anti-coagulant agents,including dextan, heparin, LMW heparin (Enoxaparin, Dalteparin),hirudin, recombinant hirudin, anti-thrombin, synthetic antithrombins,thrombin inhibitors, Warfarin (and other coumarins); anti-mitotic,antiproliferative and cytostatic agents, including vincristine,vinblastine, paclitaxel, methotrexate, cisplatin, fluorouracil,rapamycin, azathioprine, cyclophosphamide, mycophenolic acid,corticosteroids, colchicine, nitroprusside; antiangiogenic andangiostatic agents, including paclitaxel, angiostatin and endostatin;genetic materials and oligonucleotides; ACE inhibitors (e.g. Cilazapril,Lisinopril, Captopril); growth factor (e.g. VEGF, FGF) antagonists;antioxidants and vitamins (e.g. Probucol, Tocopherol); calcium channelblockers (e.g. nifedipine); fish oil (omega 3-fatty acid);phosphodiesterase inhibitors (e.g. dipyridamole); nitric acid donor(e.g. Molsidomine); somatostatin analogues (e.g. angiopeptin);immunosuppresives and anti-inflammatory agents (e.g. prednisolone,glucocorticoid and dexamethasone); antimicrobials (e.g. rifamycin) andradionuclides, including alpha, beta and gamma emitting isotopes (e.g.Re-188, Re-186, 1-125, Y-90); COX-2 inhibitors such as Celecoxib andVioxx; kinase inhibitors, such as epidermal growth factor kinaseinhibitor, tyrosine kinase inhibitors, MAP kinase inhibitors proteintransferase inhibitors, Resten-NG, and other biologically active agentsand biologic response modifiers, and others, alone or in combinations toexert multiple actions simultaneously in order to prevent restenosis,and provide other desired biological effects.

The amount of active agent loaded in coatings which have been producedaccording to the invention has been in the range of about 25 to about600 micrograms, although lower and higher loadings may be used dependingon a variety of factors, including the drug, the desired dosage level,the drug release layer composition, the type of stent, the diameter andlength of stent, the number of layers and how the active agent isapplied, the coating thickness, the chemical characteristics of theactive agent, and other factors. These factors are adjusted to provide adurable coating that controllably releases the desired amount of activeagent over an extended period. In a typical desired release pattern, 25%of the active agent is released in the first few days, the remainderbeing released gradually over 30 or more days. Other release patternsmay readily be achieved using the inventive methods and compositions,depending on the therapeutic effect desired (e.g. anti-angiogenesis,anti-cancer, etc.).

The hybrid polymer layers of the invention possess physical propertiesthat enable their useful application on stents. For instance, the hybridpolymers of the invention achieve excellent adhesion on the metallicstent surfaces. The adhesion of the hybrid polymer layers of theinvention is made possible by the use of certain bonding layers asdescribed in U.S. Pat. No. 5,997,517, incorporated herein by referencein its entirety.

Furthermore, the hybrid polymers of the invention, together with themulti-layer composite structure, ensure that the drug layers will remainwell adhered to the stent surface, even during expansion of the stent,and will not lose their adhesion during prolonged implantation. Thepolymers of the invention do not alter the mechanical stent functions,such as forces required for expansion and strength so that the stentwill resist collapsing after implantation.

In one embodiment of the invention, the production of stents can beginwith the application of the bonding primer layer. In one embodiment, theprimer layers can be on the order of about 0.1 to about 5 microns thick.Cross-linked primer layers can be thinner than non-cross-linked layers.The primer layer can be applied by dipping the stent in the primercoating solution, followed by drying at elevated temperatures in orderto drive off the solvents in the coating solution, and to cure andcross-link the primer layer.

The primer layer may be subjected to turbulent airflow to open anybridging that occurs prior to the curing step. It is also possible tospray the primer coating onto the stent. Typical curing schedulesinclude drying for fifteen to sixty minutes at 100° C. to 120° C. Thehybrid polymer primer layers comprise polymeric alloys that include suchpolymers and copolymers as acrylate polymers and copolymers, especiallythose having functional groups including amine, hydroxyl, and carboxyl,etc., epoxy resins, amine resins, ethylene acrylic acid copolymers,polyurethanes (especially more hydrophobic versions), copolymers ofpolyvinylpyrrolidone such as with vinyl acetate, polyether sulfones, andothers.

The use of one or more intermediate layers is optional, althoughpreferred. The intermediate layer can be applied over the primer layerusing substantially the same methods as described for the primer layer,including similar curing schedules at elevated temperatures. Theintermediate layer is employed to enhance the flexibility, elasticity,and expandability properties of the composite coating layers. It isrecognized that thin layers in a composite when constructedappropriately will acquire the properties of its components. Theintermediate layer is intended to contribute to and enhance theflexibility, elasticity, and expandability properties of the compositelayers. An example of a polymer which performs well in this role is apolycarbonate-polyurethane having a flexural modulus (1% secant modulus(psi) (ASTM procedure D790)) greater than 1,000 or 3,000, and elongationat break greater than 200% or 300%. In a typical embodiment, the primerlayer preferably would be about 0.1 to about 5 microns thick, and theintermediate layer would be about 0.1 to about 15 microns thick. This isbecause it is intended that the ultra flexible intermediate layercontributes substantially to the flexibility of the composite coating,and therefore preferably is at least as thick as the adjacent layers.

In practice, the invention employs polymers and copolymers which areuseful in the intermediate layer and include vinyl acetals, especiallypolyvinyl butyral, polyurethanes which are more flexible and elastic andexpandable, polycarbonate polyurethanes are especially useful for thispurpose, acrylate polymers and copolymers which are elastic, flexible,and expandable. Other polymers and copolymers could also be used in thisapplication, provided that they contribute the appropriate physicalproperties, are compatible and adherent to the adjacent layers, and arebiocompatible.

The drug releasing hybrid polymer layer can comprise two or morepolymers, together with one or more drugs, which can be dissolved in anorganic solvent or solvent mixture. The drug(s) are usually dissolved inthe organic solvent mixture, but may also be present as dispersions ofsolid particles. The hybrid polymer matrix forms a polymeric alloy upondrying. In the preferred embodiment, this layer can be typically about 1to about 10 microns thick. The hybrid polymer matrix can be applied asone layer, or as two or more layers, and different drugs may be presentin the same or different layer(s). When multiple layers are employed,the different layers could have the same or different drug releaseproperties.

Soluble drugs can also form into the polymeric alloy at the molecularlevel. An organic solvent or solvent mixture can be selected so that itis a mutual solvent for the polymeric and soluble drug components, whilein the liquid form, and throughout the drying process. It is alsopreferable if the solvent has the ability to swell the substrate,thereby enabling some of the drug-hybrid polymer components to penetratesuperficially into the substrate surface and gain improved adhesion. Thepolymeric components of the drug releasing layer can comprise celluloseesters to stabilize and preserve the drug components, and usuallycontain relatively hydrophilic polyurethane. The polyurethanecontributes flexibility, elasticity, and expandability to thedrug-releasing layer. Other polymers may also be incorporated into thelayer, including hydrophilic, water soluble polymers suchpolyvinylpyrrolidone (PVP), PVP copolymers, polyethylene glycol,polyethylene oxide water soluble cellulose ethers and esters suchhydroxymethylcellulose, others. Drugs selected from the groups that werepreviously cited may be incorporated, alone or in combinations.

In one embodiment of the invention, the coating solutions are preparedby first dissolving the polymer components in the solvent mixtures. Itis also possible to dissolve the individual polymer componentsseparately in solutions, and then to combine together separate solutionsof the individual polymers. The drug(s) are then usually incorporatedinto the hybrid polymer solution, although the drugs can be added beforethe polymers. The drug releasing coating is then applied over the stent,which already has one, or more polymer coatings, using the same methodsas used for the other polymer coatings. After coating, the coating isdried for five to sixty minutes at temperatures of 40° C.-120° C.

The coated stents can be packaged and sterilized. Ethylene oxide isuseful for sterilization of stents prepared according to the invention.

The following examples are intended to illustrate embodiments of theinvention and are not intended to limit the scope of the invention. Itshould be understood that the concentrations of the components of thesolutions of the examples may be varied within the scope of theinvention and that the components may be used in different combinations,and with additional or different polymers as described above.

In coatings of the invention, the primer (bonding) layer uses a polymercombination of

(1) acrylate/carboxyl polymer+epoxy polymer+polyvinylpyrrolidonevinylacetate copolymer (PVP/VA) or

(2) ethylene acrylic acid copolymer (EAA)+epoxy polymer+polycarbonateurethane.

Other polymers may be used in this role, including polyimide copolymers,polyamide copolymers, polyether sulfone polymers, polyethylene glycolpolymers, polyethylene oxide polymers, other polymers which typicallyare used in metal primer applications.

An intermediate layer may be polycarbonate polyurethane, flexibleacrylate polymers/copolymers including butyl acrylate, polyvinylbutyral, other elastic polymers used alone or in hybrid polymercombinations.

A drug release layer polymer combinations suitable for use with theinvention are acrylate/carboxyl polymer+epoxypolymer+polyvinylpyrrolidone vinylacetate copolymer (PVP/VA), RSNitrocellulose plus any of the following:

-   -   polytetramethylene ether glycol urethane,        polycarbonate-urethanes, PVP, polyethylene glycol, polyethylene        oxide, Methylvinylether maleicanhydride copolymer, and/or        Poly(2-hydroxyethyl methacrylate).

Active ingredients used with these combination coatings includepaclitaxel, benzalkonium heparinate, rifamycin, and methotrexate

These polymer combination and the ratios specified in the examples arenot limiting, and other suitable combinations and ratios may be used aslong as they provide the desired adhesion and drug release effects ofthe invention.

In the following examples: Polyurethane 1 is a polycarbonate urethane;Polyurethanes 2 and 3 are polytetramethylene ether glycol urethanes;Cellulose Ester 1 is RS Nitrocellulose, 1/4 sec grade; Cellulose Ester 2is RS Nitrocellulose, 5-6 sec grade. The terms nitrocellulose andcellulose nitrate are also used for these latter compounds.

Example 1

The following solutions were prepared:

Composition 1 Acrylate/carboxyl polymer, 55.5% solution (1) 8.33 gmTetrahydrofuran (THF) 39.58 gm  Cyclohexanone 41.60 gm  PVP/VA PolymerSolution (2) 2.73 gm Ethanol 1.37 gm Epoxy Polymer Solution (3) 1.20 gmComposition 2 Epoxy Polymer Solution (3) 2.56 gm PVP/VA Polymer Solution(2) 2.79 gm Acrylate/carboxyl polymer, 55.5% Solution (1) 8.50 gmCyclohexanone 42.70 gm  THF 36.70 gm  Ethanol 5.56 gm Paclitaxel 1.00 gm(1) This copolymer solution is 55.5% (w/w) solids in aromatic 150/butylcellosolve, 87.5/12.5. (2) This copolymer solution is 50.0% (w/w) solidsin ethanol. (3) This epoxy polymer is 75% (w/w) solids in xylene

Composition 1 was coated on stainless steel coronary stents, and driedfor 60 minutes at 120° C. This layer was applied twice. Composition 2was then coated over the primer layers, and dried for 60 minutes at 120°C. Drug loading on the stents in the range of 50-60 μg was achieved byapplying composition 2 three times and drying after each application.The stent samples with three layers of composition 2 were subjected toelution in room temperature phosphate buffered saline for times up to336 hours, and produced the following results tabulated in TABLE 1.

TABLE 1 Release Characteristics for Paclitaxel Extracts Analysis #1Analysis #2 Average Sample Paclitaxel Paclitaxel Paclitaxel in ExtractIdentification and Conc. Conc. Eluent volume Elution Time (μg/ml)(μg/ml) (μg/ml) (ml) Sample 1, 0.6 0.7 0.65 1.5 2 hr. Sample 1, 0.5 0.50.50 1.5 4 hr. Sample 1, 0.4 0.4 0.40 1.5 6 hr. Sample 1, 0.3 0.4 0.351.5 8 hr. Sample 1, 0.3 0.3 0.30 1.5 24 hr. Sample 1, 0.3 0.3 0.30 1.548 hr. Sample 1, 0.4 0.4 0.40 1.5 168 hr. Sample 1, 0.3 0.3 0.30 1.5 216hr. Sample 1, 0.3 0.3 0.30 1.5 336 hr. % of Total Elution PaclitaxelSample μg Paclitaxel Time Release Identification and Paclitaxel releasedover Cumulative Cumulative Elution Time Released 336 hours Hrs. μgSample 1, 0.98 18.6 2 0.98 2 hr. Sample 1, 0.75 14.3 4 1.73 4 hr. Sample1, 0.60 11.4 6 2.33 6 hr. Sample 1, 0.53 10.0 8 2.85 8 hr. Sample 1,0.53 10.0 8 2.85 8 hr. Sample 1, 0.45 8.6 24 3.30 24 hr. Sample 1, 0.458.6 48 3.75 48 hr. Sample 1, 0.60 11.4 168 4.35 168 hr. Sample 1, 0.458.6 216 4.80 216 hr. Sample 1, 0.45 8.6 336 5.25 336 hr.

The data show that approximately 10% of the paclitaxel eluted out over aperiod of 14 days. The data plotted in FIG. 1 show the cumulativequantity of paclitaxel eluted, in micrograms, over a period of 336 hours(14 days). While not wishing to be bound thereby, it is believed thatthe rate of drug elution is independent of the number of coated layers,and that the total amount of eluted drug and length of elution time areinfluenced by the amount of or the number of coatings of the drugreleasing layer, the hydrophilicity of the layer(s), and the solubilityof the drug(s) in the medium into which it/they are being released.

Example 2

This example provides a composite coating of three flexible polymer orhybrid polymer layers. The hybrid polymer bonding layer solution wasapplied and dried at 120° C. for 60 minutes. An intermediate layer wasapplied and dried at 120° C. for 60 minutes. The drug release hybridpolymer layer was applied and dried at 75° C. for 60 minutes. A highboiling point solvent was included in each formulation to aid inprocessing. Drug(s) can be imbibed into the drug release hybrid polymerlayer, but the preferred method is to add the active agents to thecoating liquid so that the drug/polymer layer can be controlled.

(All values are wt/wt %, unless otherwise specified)

Bonding Layer

Polyurethane 1 0.78% EAA 3.05% Epoxy 0.90% Dimethyl acetamide (DMAC)2.67% Cyclohexanone 33.66% THF 58.94%

Intermediate Layer

Polyurethane 1 8.80% DMAC 66.20% Cyclohexanone 25.00%

Drug Release Hybrid Polymer Layer

Polyurethane 2 6.07% Cellulose ester 1 2.43% THF 54.64% Ethanol 21.85%DMSO 15.01%

Stent samples coated with this example had good uniformity based on dyetesting. Coated stents that were expanded proved quite flexible anddemonstrated excellent adhesion to the substrate.

Example 3

This example considers a composite coating of three flexible polymer orhybrid polymer layers. A hybrid polymer bonding layer solution wasapplied and dried at 120° C. for 60 minutes. An intermediate layer wasapplied and dried at 120° C. for 60 minutes. A drug release hybridpolymer layer, as outlined below, was applied and dried at 75° C. for 60minutes. The drug release hybrid polymer layer contains one additional,ultra hydrophilic component that was not included in Example 2. It wasexpected that Example 3 would elute more rapidly relative to Example 2.A high boiling solvent was included in each formulation to aid inprocessing. This drug release hybrid polymer layer is more susceptibleto having the drug imbibed into it from solution than the drug releaselayer in Example 2. The preferred method is to add the active agents tothe coating liquid to achieve better control of the drug/polymer ratio.

Bonding layer—Same as Example 2Intermediate layer—Same as Example 2

Drug Release Hybrid Polymer Layer

Polyurethane 2 5.05 Polyurethane 3 2.17 Cellulose ester 2 1.28 THF 46.75Ethanol 29.75 DMSO 15.00

Stent samples coated with this example had good uniformity based on dyetesting. Coated stents that were expanded demonstrated good flexibilityand adhesion to the substrate, and did not crack.

Example 4

This example considers a composite coating of 3 flexible polymer orhybrid polymer layers. A bonding layer solution was applied and dried at120° C. for 60 minutes. An intermediate layer was applied and dried at120° C. for 60 minutes. A drug release hybrid polymer layer was appliedand dried at 75° C. for 60 minutes. (Example 3 is desirable as comparedto Example 5 due to high boiling solvents (e.g., a boiling point overabout 110° C.) for processing, and lower viscosity solutions (e.g.,about 20-70 cps), which are desired ranges for coating liquids.

Bonding Layer

Polyurethane 1 0.80 EAA 3.90 Epoxy 1.15 DMAC 3.40 Cyclohexanone 15.60THF 75.15

Intermediate Layer

Polyurethane 1 11.7 DMAC 88.3

Drug Release Hybrid Polymer Layer

Polyurethane 2 7.14 Cellulose ester 1 2.86 THF 64.29 Ethanol 25.71

The embodiment of Example 3 is preferred over that of Example 4 sincehigh boiling solvents were incorporated in the drug release hybridpolymer layer in that example, which improves processing, makes iteasier to prevent the coating from bridging between the struts of thestent, and provides lower solution viscosity.

Example 5

This example concerns a composite coating of two flexible polymer orhybrid polymer layers. No bonding layer was applied. Solution wasapplied and dried at 120° C. for 60 minutes. Drug release hybrid polymerlayer was applied and dried at 75° C. for 60 minutes.

Intermediate Layer

Polyurethane 1 11.7 DMAC 88.3

Drug Release Hybrid Polymer Layer

Polyurethane 2 7.14 Cellulose ester 1 2.86 THF 64.29 Ethanol 25.71

Example 3 is preferred over this example 5 due to improved compositeintegrity credited to the adhesion imparted by the bonding layer.Specifically, the composite of Example 3 showed strong adhesion to thesubstrate when abraded by rubbing with a finger when immersed in waterat room temperature. The composite coating of this example showed somebreakdown/delamination when wet rubbed during water immersion.

Example 6

In this example, two drugs (paclitaxel and benzalkonium heparinate) werecombined together in the drug release layer and were coated on astainless steel stent. The bonding layer was applied by dip coating, andexcess coating was blown off with nitrogen, and dried for 30 minutes at100° C. The intermediate layer was applied by dip coating, and excesscoating was blown off with nitrogen, and dried for 30 minutes at 100° C.The drug release layer was applied by dip coating, excess coating wasblown off with nitrogen, and was dried for 60 minutes at 75° C.

Bonding Layer

Polyurethane 1 0.79% EAA 3.06% Epoxy 0.90% Cyclohexanone 33.64% DMAC2.67% THF 58.94%

Intermediate Layer

Polyurethane 1 8.80% DMAC 66.20% Cyclohexanone 25.00%

Drug Release Layer

Polyurethane 2 5.89% Nitrocellulose 2 2.36% THF 53.00% Ethanol 21.19%DMSO 14.56% Paclitaxel 1.00% Benzalkonium heparinate 2.00%

This example showed good coating uniformity, good wet abrasionresistance, and good adhesion to the metal stent surface.

Example 7

This example is similar to Example 6, except that the drug release layercontained only benzalkonium heparinate. The coatings were applied on astainless steel stent using the same procedures as in Example 6.

Bonding layer—same as previous examplesIntermediate layer—same as previous examples

Drug Releasing Layer

Polyurethane 2 5.89% Nitrocellulose 2 2.36% THF 53.00% Ethanol 21.19%DMSO 14.56% Benzalkonium heparinate 3.0%

This example also showed good coating uniformity, good wet abrasionresistance, and good adhesion to the metal stent surface.

Example 8

This example is similar to Example 6, except that the drug release layercontained rifamycin. The coatings were applied on a stainless steelstent using the same procedures as in Example 6.

Bonding layer—same as previous examplesIntermediate layer—same as previous examples

Drug Release Layer

Polyurethane 2 5.89% Nitrocellulose 2 2.36% THF 53.00% Ethanol 21.19%DMSO 14.56% Rifamycin 3.00%

Example 9

In this example methotrexate was imbibed into the drug releasing layerfrom an aqueous solution. The bonding layer and intermediate layer arethe same as were used in Example 6, and were applied using the sameprocedures.

Bonding layer—same as aboveIntermediate layer—same as above

Drug Release Layer

Polyurethane 2 6.07% Nitrocellulose 2 2.43% THF 54.64% Ethanol 21.85%DMSO 15.01%

The drug release layer was applied and treated as in Example 8. Afterthe oven curing process, the stent was cooled to room temperature, andthen briefly immersed in an aqueous solution of methotrexate, 25 mg/ml.,and air dried. The coating absorbed drug from the aqueous solution.

Example 10

Stents were coated with the following primer (BOND-COAT®, STSBiopolymers, Inc.) layer and intermediate layer, and dried 15 minutes at100° C., after each application.

BOND-COAT® Primer Layer

Polycarbonate polyurethane 0.78% Ethylene acrylic acid copolymer 3.05%Epoxy resin 0.90% DMAC 2.67% Cyclohexanone 33.66% THF 58.94%

Intermediate Layer

Polycarbonate polyurethane 1.28% DMAC 71.67% Cyclohexanone 27.05%

Next, the stent was coated with the following drug reservoir layer, anddried for 15 minutes at 75° C.

Drug Reservoir Layer

Polycarbonate polyurethane  2.5 gm Cellulose nitrate  1.0 gm Methylethyl ketone 30.0 gm n-Butanol 20.0 gm Dimethylacetamide 41.4 gmCyclohexanone 27.6 gm Paclitaxel  2.0 gm Silicone polyurethane  2.5 gm

This solution coated uniformly, and resulted in a smooth, clear layer.

Example 11

A coronary stent was coated with the primer and intermediate layers asin Example 10. Next, the stent was coated with the following drugreservoir layer, and dried using the same schedule as in Example 10.

Drug Reservoir Layer

Cyclohexanone 6.29 gm Dimethylacetamide 4.31 gm n-Butanol 4.40 gmPolyethylene glycol 3350 0.37 gm Cellulose nitrate 0.15 gm Paclitaxel0.015 gm 

This solution coated uniformly, and resulted in a smooth, clear layer.

Example 12

A coronary stent was coated with the primer and intermediate layers asin Example 10. Next, the stent was coated with the following drugreservoir layer, and dried using the same schedule as in Example 10.

Drug Reservoir Layer

Tetrahydrofuran 7.0 gm Dimethylacetamide 4.0 gm Cyclohexanone 6.0 gmMethylvinylether maleic anhydride copolymer 0.37 gm  Cellulose nitrate0.03 gm  Paclitaxel 0.015 gm 

This solution exhibited solvent attack on the intermediate layer duringcoating.

Example 13

A coronary stent was coated with the primer and intermediate layers asin Example 10. Next, the stent was coated with the following drugreservoir layer, and dried using the same schedule as in Example 10.

Drug Reservoir Layer

Dimethylacetamide 8.0 gm Benzyl alcohol 8.0 gm Poly(2-hydroxyethylmethacrylate) 0.25 gm  Paclitaxel 0.019 gm 

This solution coated uniformly, and resulted in a smooth, clear layer.

Example 14

A coronary stent was coated with the primer and intermediate layers asin Example 10. Next, the stent was coated with the following drugreservoir layer, and dried using the same schedule as in Example 10.

Drug Reservoir Layer

Polycarbonate polyurethane  2.5 gm Cellulose nitrate  1.0 gm Methylethyl ketone 30.0 gm n-Butanol 20.0 gm Dimethylacetamide 18.9 gmCyclohexanone 27.6 gm Paclitaxel  2.0 gm

This solution coated uniformly, and resulted in a smooth, clear layer.

Stents were expanded and inspected for cracking and adhesion failure. Nocracking or chipping off was observed after stent expansion. Severalcoated stents were incubated in 37° C. phosphate buffered saline (PBS)for various times up to 10 days. Stents were removed from the serum attheir designated time points, and soaked in acetonitrile to remove thecoating. The acetonitrile extract was tested via HPLC to determine howmuch paclitaxel remained on each stent after its incubation period.60.4% of the starting Paclitaxel remained on stents after 10 days ofincubation on PBS.

Example 15

This comparative example evaluates adhesion of gelatin and human albuminon metal stents.

Experiment

Stainless steel stents were coated with two biodegradable polymersolutions, 5% gelatin and 5% human albumin and tested for adhesion.

Materials

Commercial 15 mm stainless steel stents

VEE GEE 150 Bloom Type A Economix Gelatin, Vyse Gelatin Company

5% human albumin solution, Alpha Therapeutic Corporation1,1,1 trichloroethane, EM Sciencestainless steel tabs, 1 cm×8 cmTriton X-100 nonionic surfactant, Ruger Chemical Company

Protocol

Prepare a 5% w/w solution of the gelatin by dissolving 5 g of gelatin in95 g of filtered deionized water. Add 0.4% w/w Triton X-100 by mixing0.1 g of Triton X-100 to 24.9 g of 5% w/w gelatin solution.

Human albumin comes as a 5% w/v solution. Add 0.4% w/w Triton X-100 bymixing 0.1 g of Triton X-100 to 24.9 g of 5% w/v human albumin solution.

Clean the steel tabs with 1,1,1 trichloroethane then coat with each ofthe polymer solutions by dip coat methods. Use a 5-second dwell time andapproximately 3 cm/s draw speed. Allow samples to air-dry for ½ hour atroom temperature then oven dry for one hour at 45° C. Test adhesionusing the so-called tape test method, in which a strip of Scotch 810Tape is firmly pressed onto the coated surface, and then pulled offabruptly. The coated article and the tape are inspected to see if any ofthe coating was stripped off of the coated surface. No coating should beremoved by this test. This test method has been widely accepted for manyyears by members of the coating industry as a useful predictor of coatedproduct performance in use.

Repeat steel tab procedure using the 15 mm stainless steel stents,except add one step. After drawing the sample from the coating solutionuse helium to blow any excess polymer off the stent. (Remove any polymerthat may be filling the holes in the stent.)

Results/Summary

The coating solutions both produce a uniform coating on the steel tabs.However, the tape dry adhesion tests show that both coatings failed. Noother tests were preformed since they failed in the first test.

The coated stents were dyed with a Gentian Violet solution and comparedto a dyed uncoated stent. The stent pieces were dipped into the solutionand blotted dry with a paper towel. Both the coated stents showed abright purple color while the uncoated stent did not show the brightpurple color. This shows that the stents were covered with the polymercoatings. The samples underwent the dry adhesion tape test and wereobserved under a microscope. Polymer strands were seen to be coming off,showing the samples failed the adhesion test. No other tests wereperformed since they failed the first test.

CONCLUSION

The gelatin and human albumin polymers produce coatings that fail toadhere to steel tabs or stainless steel stents. The inventive coatingswere far superior.

1-29. (canceled)
 30. A method for making a medicated stent comprising:applying a primer polymer liquid comprising one or more polymers in avolatile medium, applying a drug reservoir polymer liquid comprising oneor more polymers in a volatile medium, the one or more drug reservoirpolymers being different from the one or more primer layer polymers, andapplying an active agent either together with or after applying the drugreservoir polymer liquid, and removing the volatile media, the layersbeing applied without forming coating bridges between struts of thestent, the layers remaining intact upon stent insertion and expansion ata therapeutic site of a subject, and releasing efficacious amounts ofthe active agent at the therapeutic site.
 31. The method of claim 30,comprising applying more than one active agent.
 32. The method of claim30, comprising repeating one or more of the applying steps.
 33. Themethod of claim 30, further comprising applying an intermediateflexibilizing polymer liquid comprising one or more polymers that differfrom the one or more polymers of the primer layer and the drug reservoirlayer.
 34. The method of claim 30, wherein the volatile media have aboiling point greater than about 110 degrees C.
 35. The method of claim30, wherein the liquids have a viscosity between about 20 and about 70cps.
 36. A method for making a medicated stent comprising applying aprimer polymer layer and a drug reservoir layer comprising at least twopolymers and one or more active agent(s), wherein the polymercompositions of the primer and drug reservoir are different, withoutforming coating bridges between struts of the stent, the coatingremaining intact upon stent expansion, and releasing efficacious amountsof the active agent(s).
 37. A method for administering a bioactive agentto a target site in a subject, comprising: implanting a stent at thetarget site of the subject, the stent comprising a coating having aprimer layer and a drug release layer, the drug release layer comprisingthe bioactive agent, and the primer and drug release layers comprisingdifferent polymers, expanding the stent, and allowing the bioactiveagent to elute from the coating during an extended period, the coatingremaining intact during implanting, during stent expansion, and duringthe extended period.
 38. (canceled)